5-Fluorooxindole-3-carboxylic acid ester

ABSTRACT

A 5-fluorooxindole-3-carboxylic acid ester represented by a formula (2):  
                 
         wherein R 1  is a group selected from the group consisting of an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted cycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 7 to 10 carbon atoms or an aryl group having 6 to 14 carbon atoms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of Ser. No. 10/333,316,filed Jan. 16, 2003, which is a U.S. National Phase Application under 35U.S.C. 371 of International Application No. PCT/JP01/06260 (notpublished in English) filed Jul. 19, 2001.

TECHNICAL FIELD

The present invention relates to a process for preparing5-fluorooxindole and a process for preparing its preparationintermediates, more specifically to a process for preparing5-fluorooxindole which is useful as a synthetic intermediate for amedicine such as an anticancer agent or anti-inflammatory and analgesicagent and a simple and easy process for preparing2-(5-fluoro-2-nitrophenyl)-2-substituted acetic acid ester which is apreparation intermediate.

BACKGROUND ART

As a conventional method for preparing a2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundfrom 2,4-dihalogenonitrobenzene compound, it has been known a method ofsynthesizing dimethyl 2-(5-halogeno-2-nitrophenyl)malonate by reactingdimethyl malonate with 2,4-dihalogenonitrobenzene in the presence ofsodium hydride in dimethyl sulfoxide (Synthesis, 1993, 51). However,according to this method, complicated operations are required sincesodium hydride having highly ignitable property is used and the reactiongenerates a hydrogen gas, so that it has problems as an industrialproduction process.

Also, as a process for producing 5-fluorooxindole from2-(5-fluoro-2-nitrophenyl)malonic acid diester which is a kind of theabove-mentioned 2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acidester, it has been described in Synthesis, 1993, 51, a process forproducing 5-fluorooxindole by reacting lithium chloride with dimethyl2-(5-fluoro-2-nitrophenyl)malonate in a mixed solvent of water anddimethyl sulfoxide to once form methyl 5-fluoro-2-nitrophenylacetate,and then, reducing the resulting compound in acetic acid in the presenceof iron and cyclizing the resulting compound. However, according to thisprocess, there are problems that the reaction system is complicated anda total yield of the objective compound is as low as 49%.

An object of the present invention is to solve the above-mentionedproblems and to provide an industrially suitable process for preparing5-fluorooxindole from an easily available2-(5-fluoro-2-nitrophenyl)malonic acid diester with a simple and easymethod and a high yield.

A further object of the present invention is to solve theabove-mentioned problems and to provide an industrially suitable processfor preparing a 2-(5-halogeno-2-nitrophenyl)malonic acid diestercompound from a 2,4-dihalogenonitrobenzene compound with a simple andeasy method.

A still further object of the present invention is to provide a novel5-fluorooxindole-3-carboxylic acid ester and a2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundwhich are useful as synthetic intermediates of the above-mentionedpreparation processes.

SUMMARY OF THE INVENTION

The present invention is to provide a process for preparing5-fluorooxindole represented by the formula (3):

which comprises (A) a first step of cyclizing2-(5-fluoro-2-nitrophenyl)malonic acid diester represented by theformula (1):

-   -   wherein R¹ and R may be the same or different from each other        and each represents a group which does not participate in the        reaction,        under reductive conditions to form 5-fluorooxindole-3-carboxylic        acid ester represented by the formula (2):    -   wherein R¹ has the same meaning as defined above, and        (B) then, a second step of decarboxylating the        5-fluorooxindole-3-carboxylic acid ester.

The present invention also provides 5-fluorooxindole-3-carboxylic acidester represented by the formula (2):

-   -   wherein R¹ represents a group which does not participate in the        reaction.

The present invention also provides a process for preparing a2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundrepresented by the formula (6):

-   -   wherein R³, R⁴ and R⁵ each represents a group which does not        participate in the reaction, R⁶ represents an alkoxycarbonyl        group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, an        acyl group or a cyano group, R⁷ represents a group which does        not participate in the reaction, and X² represents a halogen        atom,        which comprises reacting a 2,4-dihalogenonitrobenzene compound        represented by the formula (4):    -   wherein R³, R⁴, R⁵, and X² have the same meanings as defined        above and X¹ represents a halogen atom,        with a 2-mono-substituted acetic acid ester compound represented        by the formula (5):    -   wherein R⁶ and R⁷ have the same meanings as defined above, in        the presence of a metal alkoxide (s) or a metal inorganic acid        salt(s) and in an organic solvent(s).

The present invention further provides a2-(5-halogeno-2-nitrophenyl)-2-acylacetic acid ester compoundrepresented by the formula (7):

-   -   wherein R³, R⁴, R⁵, R⁷ and X² have the same meanings as defined        above, and R⁸ represents an alkyl group, an aralkyl group or an        aryl group,        and a 2-(5-halogeno-2-nitrophenyl)-2-cyanoacetic acid ester        compound represented by the formula (8):    -   wherein R³, R⁴, R⁵, R⁷ and X² have the same meanings as defined        above.

BEST MODE FOR CARRYING OUT THE INVENTION

The process for preparing 5-fluorooxindole of the present inventioncomprises two steps of

-   (A) a first step of cyclizing a 2-(5-fluoro-2-nitrophenyl)malonic    acid diester represented by the formula (1) under reductive    conditions to form a 5-fluorooxindole-3-carboxylic acid ester    represented by the formula (2), and-   (B) then, a second step of decarboxylating the    5-fluorooxindole-3-carboxylic acid ester,    to obtain 5-fluorooxindole as a reaction product.

Subsequently, the above two steps are explained successively.

(A) The First Step

The first step of the present invention is a step of cyclizing2-(5-fluoro-2-nitrophenyl)malonic acid diester represented by theformula (1) under reductive conditions to obtain5-fluorooxindole-3-carboxylic acid ester represented by the formula (2).

The 2-(5-fluoro-2-nitrophenyl)malonic acid diester to be used in thefirst step of the present invention is represented by theabove-mentioned formula (1). In the formula (1), R¹ and R² may be thesame or different from each other, and each represents a group whichdoes not participate in the reaction, more specifically, there may bementioned, for example, an alkyl group, a cycloalkyl group, an aralkylgroup or an aryl group.

As the above-mentioned alkyl group, an alkyl group having 1 to 10 carbonatoms is particularly preferred, and there may be mentioned, forexample, a methyl group, an ethyl group, a propyl group, a butyl group,a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonylgroup, a decyl group and the like. These groups may include variouskinds of isomers.

As the above-mentioned cycloalkyl group, a cycloalkyl group having 3 to7 carbon atoms is particularly preferred, and there may be mentioned,for example, a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, a cycloheptyl group and the like. Thesegroups may include various kinds of isomers.

As the above-mentioned aralkyl group, an aralkyl group having 7 to 10carbon atoms is particularly preferred, and there may be mentioned, forexample, a benzyl group, a phenethyl group, a phenylpropyl group and aphenylbutyl group. These groups may include various kinds of isomers.

As the above-mentioned aryl group, an aryl group having 6 to 14 carbonatoms is particularly preferred, and there may be mentioned, forexample, a phenyl group, a tolyl group, a naphthyl group, an anthranylgroup and the like. These groups may include various kinds of isomers.

The first step of the present invention is not specifically limited solong as it is a reductive method generally carried out, and it ispreferably carried out in the presence of a catalyst under hydrogenatmosphere.

As the above-mentioned catalyst, there may be mentioned those containingat least one metal atom selected from the group consisting of palladium,platinum and nickel, more specifically there may be mentioned, forexample, palladium/carbon, palladium/barium sulfate, palladiumhydroxide/carbon, platinum/carbon, palladium-platinum/carbon, platinumoxide, Raney nickel and the like, and palladium/carbon is preferablyused.

An amount of the above-mentioned catalyst to be used is preferably 0.01to 1.0% by weight, more preferably 0.05 to 0.5% by weight in terms of ametal atom based on the amount of 2-(5-fluoro-2-nitrophenyl)malonic aciddiester. Incidentally, these catalysts may be used singly or incombination of two or more.

The first step of the present invention is preferably carried out in thepresence of a solvent. As the solvent to be used, it is not specificallylimited so long as it does not inhibit the reaction, and there may bementioned water; alcohols such as methanol, ethanol and the like; esterssuch as methyl acetate, ethyl acetate and the like; aromatichydrocarbons such as benzene, toluene and the like; ethers such astetrahydrofuran, dioxane and the like, and preferably water, alcoholsand/or ethers is/are used, more preferably water, methanol and/orethanol is/are used.

An amount of the above-mentioned solvent to be used is optionallycontrolled depending on uniformity or stirrability of the solution, andis preferably 3 to 50-fold weight, more preferably 5 to 30-fold weightbased on the amount of 2-(5-fluoro-2-nitrophenyl)malonic acid diester.Incidentally, these solvents may be used singly or in combination of twoor more.

The first step of the present invention is carried out, for example, ina hydrogen atmosphere, by mixing 2-(5-fluoro-2-nitrophenyl)malonic aciddiester, a catalyst and a solvent and stirring them and the like. Areaction pressure at that time is preferably 0.1 to 5 MPa, morepreferably 0.1 to 2 MPa, and a reaction temperature is preferably 20 to80° C., more preferably 30 to 60° C.

In the first step of the present invention, a solution containing5-fluorooxindole-3-carboxylic acid ester as a main product can beobtained, and in the present invention, it is generally carried out,after separation of the catalyst, if necessary, the next step by usingsaid solution as such or after subjecting to concentration. However, insome cases, the formed 5-fluorooxindole-3-carboxylic acid ester is onceisolated by a general method such as recrystallization, distillation,column chromatography and the like, and then, the next step may becarried out.

Also, 5-fluorooxindole-3-carboxylic acid ester (a keto form) representedby the formula (2):

-   -   wherein R¹ has the same meaning as defined above, obtained in        the first step of the present invention is a novel compound        useful as an intermediate for 5-fluorooxindole. Incidentally, in        the solution, it is a case where it becomes equilibrium with an        enol form represented by the formula (2′)    -   wherein R¹ has the same meaning as defined above.        (B) The Second Step

The second step of the present invention is a step of decarboxylatingthe 5-fluorooxindole-3-carboxylic acid ester represented by the formula(2) obtained in the first step to obtain 5-fluorooxindole.

The second step of the present invention is not particularly limited solong as it is a decarboxylation method usually carried out, and it ispreferably carried out in the presence of an acid.

As the above-mentioned acid, there may be mentioned hydrochloric acid,sulfuric acid, nitric acid, methanesulfonic acid, acetic acid and thelike, and hydrochloric acid or sulfuric acid is preferably used.

As an amount of the above-mentioned acid to be used, it is preferablyused in an amount of 1 to 10-fold mole, more preferably 2 to 5-fold molebased on the amount of the 5-fluorooxindole-3-carboxylic acid ester.Incidentally, these acids may be used singly or in combination of two ormore.

The second step of the present invention is preferably carried out inthe presence of a solvent(s). As the solvent to be used, it is notspecifically limited so long as it does not inhibit the reaction, andthere may be mentioned water; alcohols such as methanol, ethanol,n-butyl alcohol, t-butyl alcohol and the like, ethers such astetrahydrofuran, dioxane and the like; hydrocarbons such as cyclohexane,toluene and the like, and preferably water, alcohols and/or ethersis/are used, more preferably water, methanol and/or ethanol is/are used.

An amount of the above-mentioned solvent may be optionally controlleddepending on the uniformity or stirrability of the solution, andpreferably 2 to 20-fold weight, more preferably 4 to 10-fold weightbased on the amount of the 5-fluorooxindole-3-carboxylic acid ester.Incidentally, these solvents may be used singly or in combination of twoor more.

The second step of the present invention is carried out, for example, inan inert gas atmosphere, by mixing 5-fluorooxindole-3-carboxylic acidester obtained in the first step or a reaction mixture containing thesame, an acid(s) and a solvent(s), and stirring the mixture and thelike. A reaction temperature at that time is preferably 20 to 110° C.,more preferably 50 to 90° C., and a reaction pressure is notspecifically limited.

The 5-fluorooxindole obtained in the second step of the presentinvention is separated and purified by a general method such asrecrystallization, distillation, column chromatography and the like.

Next, a process for preparing the 2-(5-halogeno-2-nitrophenyl)malonicacid diester compound which is a starting compound in theabove-mentioned reaction of the present invention is explained.

The 2,4-dihalogenonitrobenzene compound to be used in the reaction ofthe present invention is represented by the above-mentioned formula (4).In the formula (4), R³, R⁴ and R⁵ are groups which do not participate inthe reaction, and more specifically, they each represent a hydrogenatom; a halogen atom; an alkyl group, a cycloalkyl group, an aralkylgroup, an aryl group, an alkoxy group or an aryloxy group each of whichmay have a substituent(s).

As the above-mentioned halogen atom, there may be mentioned a fluorineatom, a chlorine atom, a bromine atom and an iodine atom.

As the above-mentioned alkyl group, an alkyl group having 1 to 10 carbonatoms is particularly preferred, and there may be mentioned, forexample, a methyl group, an ethyl group, a propyl group, a butyl group,a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonylgroup, a decyl group and the like. These alkyl groups may includevarious isomers.

As the above-mentioned cycloalkyl group, a cycloalkyl group having 3 to7 carbon atoms is particularly preferred, and there may be mentioned,for example, a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, a cycloheptyl group and the like. Thesecycloalkyl groups may include various kinds of isomers.

As the above-mentioned aralkyl group, an aralkyl group having 7 to 10carbon atoms is particularly preferred, and there may be mentioned, forexample, a benzyl group, a phenethyl group, a phenylpropyl group, aphenylbutyl group and the like. These aralkyl groups may include variouskinds of isomers.

As the above-mentioned aryl group, aryl group having 6 to 14 carbonatoms is particularly preferred, and there may be mentioned, forexample, a phenyl group, a tolyl group, a naphthyl group, an anthranylgroup and the like. These aryl groups may include various kinds ofisomers.

As the above-mentioned alkoxy group, an alkoxy group having 1 to 12carbon atoms is particularly preferred, and there may be mentioned, forexample, a methoxy group, an ethoxy group, a propoxy group, a butoxygroup, a benzyloxy group and the like. These alkoxy groups may includevarious kinds of isomers.

As the above-mentioned aryloxy group, an aryloxy group having 6 to 14carbon atoms is particularly preferred, and there may be mentioned, forexample, a phenoxy group, a tolyloxy group and the like. These aryloxygroups may include various kinds of isomers.

The above-mentioned alkyl group, cycloalkyl group, aralkyl group, arylgroup, alkoxy group or aryloxy group may have a substituent(s). As thesubstituent(s), there may be mentioned at least one selected from asubstituent formed through a carbon atom, a substituent formed throughan oxygen atom and a substituent formed through a nitrogen atom.

As the above-mentioned substituent formed through a carbon atom, theremay be mentioned, for example, an alkyl group such as a methyl group, anethyl group, a propyl group and the like; an aralkyl group such as abenzyl group and the like; an aryl group such as a phenethyl group andthe like; and a cyano group.

As the above-mentioned substituent formed through an oxygen atom, theremay be mentioned, for example, an alkoxy group such as a methoxy group,an ethoxy group, a propoxy group, a butoxy group, a benzyloxy group andthe like; an aryloxy group such as a phenoxy group and the like.

As the above-mentioned formed through a nitrogen atom, there may bementioned, for example, a nitro group; and an amino group.

Also, in the formula (1), X¹ and X² both represent a halogen atom, andthere may be mentioned a fluorine atom, a chlorine atom, a bromine atomand an iodine atom.

The 2-mono-substituted acetic acid ester compound to be used in thereaction of the present invention is represented by the above-mentionedformula (5). In the formula (5), R⁶ represents an alkoxycarbonyl groupsuch as a methoxycarbonyl group, an ethoxycarbonyl group, apropoxycarbonyl group, a butoxycarbonyl group and the like; anaralkyloxycarbonyl group such as a benzyloxycarbonyl group and the like;an aryloxycarbonyl group such as a phenoxycarbonyl group and the like;an acyl group such as an acetyl group, a propionyl group, a benzoylgroup and the like; and a cyano group. These groups may include variouskinds of isomers. R⁷ is a group which does not participate in thereaction, and more specifically, there may be mentioned an alkyl grouphaving 1 to 4 carbon atoms such as a methyl group, an ethyl group, apropyl group and the like; an aralkyl group such as a benzyl group andthe like; and an aryl group such as a phenyl group and the like. Thesegroups may include various kinds of isomers.

An amount of the above-mentioned 2-mono-substituted acetic acid estercompound is preferably 1.0 to 5.0-fold mole, more preferably 1.2 to3.0-fold mole based on the amount of the 2,4-dihalogenonitrobenzenecompound.

As a metal atom of the metal alkoxide to be used in the reaction of thepresent invention, there may be mentioned, for example, a Group 1A atom(Group 1 atom) such as a lithium atom, a sodium atom, a potassium atomand the like; a Group 2A atom (Group 2 atom) such as a magnesium atom, acalcium atom and the like; and a Group 3B atom (Group 13 atom) such asaluminum and the like as described in Rikagaku Jiten (Science andChemistry Dictionary), fourth edition (published by Iwanami Shoten,Japan).

As the above-mentioned metal alkoxide(s), there may be used, forexample, a Group 1A metal (Group 1 metal) alkoxide such as lithiummethoxide, sodium methoxide, potassium methoxide, sodium ethoxide,potassium ethoxide, potassium t-butoxide and the like; a Group 2A metal(Group 2 metal) alkoxide such as magnesium methoxide, calcium methoxideand the like; a Group 3B metal (Group 13 metal) alkoxide such asaluminum isopropoxide and the like.

Also, as a metal atom of the metal inorganic acid salt to be used in thereaction of the present invention, there may be mentioned, for example,an alkali metal atom such as a lithium atom, a sodium atom, a potassiumatom and the like; an alkaline earth metal atom such as a magnesiumatom, a calcium atom and the like, preferably an alkali metal atom, morepreferably a sodium atom or a potassium atom.

As an inorganic acid of the metal inorganic acid salt to be used in thereaction of the present invention, there may be mentioned, for example,carbonic acid, phosphoric acid and the like, preferably carbonic acid.

As the above-mentioned metal inorganic acid salt(s), there may bementioned, for example, sodium carbonate, sodium hydrogen carbonate,potassium carbonate, potassium hydrogen carbonate, magnesium carbonate,calcium carbonate, sodium phosphate and sodium hydrogen phosphate, andsodium carbonate or potassium carbonate is preferably used.

An amount of the above-mentioned metal alkoxide(s) or metal inorganicacid salt(s) is preferably 1.0 to 5.0-fold mole, more preferably 1.2 to3.0-fold mole based on the amount of the 2,4-dihalogenonitrobenzenecompound. These metal alkoxides or metal inorganic acid salts may beused singly or in combination of two or more.

As the organic solvent(s) to be used in the reaction of the presentinvention, it is not specifically limited so long as it does not inhibitthe reaction, and there may be mentioned, for example, ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like;aliphatic hydrocarbons such as hexane, cyclohexane and the like;aromatic hydrocarbons such as benzene, toluene, xylene and the like;amides such as N,N-dimethylformamide, N,N′-dimethylimidazolidinone andthe like; nitriles such as acetonitrile, propionitrile and the like;dimethyl sulfoxide and the like. It is preferably aliphatichydrocarbons, aromatic hydrocarbons, amides or dimethyl sulfoxide when ametal alkoxide is used, and aliphatic hydrocarbons, aromatichydrocarbons, amides, nitriles or dimethyl sulfoxide when a metalinorganic acid salt is used, and it is more preferably cyclohexane,toluene, N,N-dimethylformamide or dimethyl sulfoxide when a metalalkoxide is used, and cyclohexane, toluene, acetonitrile orN,N-dimethylformamide when a metal inorganic acid salt is used.

An amount of the above-mentioned organic solvent may be optionallycontrolled depending on uniformity or stirrability of the reactionmixture, and it is preferably 1 to 50-fold weight, more preferably 1.5to 20-fold weight based on the amount of the 2,4-dihalogenonitrobenzenecompound. These organic solvents may be used singly or in combination oftwo or more.

The reaction of the present invention can be carried out, for example,by mixing the 2,4-dihalogenonitrobenzene compound, the2-mono-substituted acetic acid ester compound, at least one of the metalalkoxide and the metal inorganic acid salt, and the organic solvent andthey are reacted. As a preferred embodiment of the present invention,the 2-mono-substituted acetic acid ester compound, at least one of themetal alkoxide and the metal inorganic acid salt, and an organic solventare mixed, and the 2,4-dihalogenonitrobenzene compound is added to theabove mixture preferably at 20 to 140° C., more preferably at 30 to 120°C. (if necessary, after removing a formed alcohol by single distillationor azeotropic distillation under the pressure of 0.001 to 0.1 MPa, orwhile removing the same) to effect the reaction. Also, when the metalinorganic acid salt is used, the reaction may be promoted by addingcrown ether or polyethylene glycol.

The 2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid estercompound which is an objective compound obtained by the reaction of thepresent invention can be separated and purified by a general method suchas column chromatography, distillation, recrystallization and the likeafter completion of the reaction.

Incidentally, a 2-(5-halogeno-2-nitrophenyl)-2-acylacetic acid estercompound represented by the formula (7):

-   -   wherein R³, R⁴, R⁵, R⁷, R⁸ and X² have the same meanings as        defined above,        and a 2-(5-halogeno-2-nitrophenyl)-2-cyanoacetic acid ester        compound represented by the formula (8):    -   wherein R³, R⁴, R⁵, R⁷ and X² have the same meanings as defined        above,        are novel compounds.

EXAMPLE

Next, the present invention will be explained by referring to Examples,but the scope of the present invention is not limited by these.

Example 1

In a flask made of glass equipped with a stirrer, a thermometer, adistillation device and a dropping funnel and having an inner volume of200 ml were charged 3.40 g (62.9 mmol) of sodium methoxide and 30 mldimethyl sulfoxide under argon atmosphere, and then, while stirring atroom temperature, 8.48 g (62.9 mmol) of dimethyl malonate with a purityof 98% was gradually added dropwise over 5 minutes. Moreover, 10 ml ofcyclohexane was added to the mixture, and after raising the temperatureto 100 to 105° C., the formed methanol was subjected to azeotropicdistillation (removed by distillation) with cyclohexane. After thisoperation (removal of methanol by distillation) was repeated twice, thereaction mixture was cooled to 70° C., and 5.10 g (31.4 mmol) of2,4-difluoronitrobenzene with a purity of 98% was gradually addeddropwise over 10 minutes, and the resulting mixture was reacted at 70 to80° C. for one hour. After completion of the reaction, the mixture wascooled to room temperature, 100 ml of toluene was added to the mixtureand 5.25 ml (31.4 mmol) of 6 mol/l hydrochloric acid was gradually addeddropwise while stirring. Then, the organic layer was separated, and theresulting mixture was washed successively with 50 ml of water and 50 mlof a saturated saline solution in this order, and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure, and the resulting concentrate was purified by silicagel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethylacetate=9:1 (volume ratio)) to obtain 5.60 g of dimethyl2-(5-fluoro-2-nitrophenyl)malonate (isolation yield: 64%) as whitecrystals with a purity of 98% (areal percentage by high performanceliquid chromatography).

Physical properties of the dimethyl 2-(5-fluoro-2-nitrophenyl)malonatewere as follows.

EI-MS (m/e); 225 (M-NO₂), CI-MS (m/e); 272(M+1)

¹H-NMR (CDCl₃, δ (ppm)); 3.82 (6H, s), 5.40 (1H, s), 7.20 to 7.35 (2H,m), 8.1 to 8.2 (1H, m)

Example 2

In a flask made of glass equipped with a stirrer, a thermometer, adistillation device and a dropping funnel and having an inner volume of500 ml were charged 11.0 g (0.2 mol) of sodium methoxide and 30 ml ofdimethyl sulfoxide under argon atmosphere, and the temperature of themixture was raised to 110 to 120° C. while stirring, then, 27.0 g (0.2mol) of dimethyl malonate with a purity of 98% was gradually addeddropwise to the mixture over 30 minutes, and the resulting mixture wasstirred for 2 hours while removing methanol under reduced pressure of0.010 to 0.013 MPa. Subsequently, the mixture was cooled to 100° C.under the same pressure, 16.2 g (0.1 mol) of 2,4-difluoronitrobenzenewith a purity of 98% was gradually added dropwise to the mixture over 30minutes, and the mixture was further reacted at the same pressure andthe same temperature for one hour. After completion of the reaction, themixture was cooled to room temperature, 100 ml of toluene was added tothe mixture and 40 ml (0.2 mol) of 5 mol/l hydrochloric acid wasgradually added dropwise to the mixture while stirring. Then, theorganic layer was separated, and washed successively with 50 ml of waterand 50 ml of a saturated saline solution in this order, and dried overanhydrous magnesium sulfate. This organic layer was analyzed (absolutequantitative method) by high performance liquid chromatography, it canbe found that 20.6 g (yield: 76%) of dimethyl2-(5-fluoro-2-nitrophenyl)malonate was formed.

Example 3

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 100ml were charged 3.40 g (62.9 mmol) of sodium methoxide and 20 ml ofdimethyl sulfoxide under argon atmosphere, and then, while stirring atroom temperature, 8.31 g (62.3 mmol) of dimethyl malonate with a purityof 99% was gradually added dropwise to the mixture over 5 minutes. Aftercooling the mixture to 20° C., 5.10 g (31.4 mmol) of2,4-difluoronitrobenzene was gradually added dropwise to the mixtureover 5 minutes, and the temperature of the mixture was raised to 80° C.and the mixture was reacted for one hour. After completion of thereaction, the mixture was cooled to room temperature, and then, 100 mlof ethyl acetate was added to the mixture, and 5.25 ml (31.4 mmol) of 6mol/l hydrochloric acid was gradually added dropwise to the mixturewhile stirring. Then, the organic layer was separated, and washedsuccessively with 30 ml of water and 30 ml of a saturated salinesolution in this order, and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureand the resulting concentrate was purified by silica gel columnchromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1(volume ratio)) to obtain 6.55 g of dimethyl2-(5-fluoro-2-nitrophenyl)malonate (isolation yield: 75%) as a whitecrystal with a purity of 97.2% (areal percentage by high performanceliquid chromatography).

Example 4

In a similar device as in Example 1 were charged 3.40 g (62.9 mmol) ofsodium methoxide and 30 ml of dimethyl sulfoxide under argon atmosphere,then, while stirring at room temperature, 6.30 g (62.9 mmol) of methylcyanoacetate with a purity of 99% was gradually added dropwise over 5minutes. Moreover, 10 ml of cyclohexane was added to the mixture, andthe temperature of the mixture was raised to 100 to 105° C., formedmethanol was subjected to distillation (azeotropic distillation) withcyclohexane. This operation (distillation of methanol) was repeatedtwice, then, the mixture was cooled to room temperature, 5.10 g (41.9mmol) of 2,4-difluoronitrobenzene with a purity of 98% was graduallyadded dropwise to the mixture over 10 minutes while maintaining thetemperature to 30 to 40° C., and the resulting mixture was reacted byraising the temperature to 75° C. for one hour. After completion of thereaction, the mixture was cooled to room temperature, then, 100 ml ofethyl acetate was added to the mixture, and 5.25 ml (31.4 mmol) of 6mol/l hydrochloric acid was gradually added dropwise to the mixturewhile stirring. Then, the organic layer was separated, and washedsuccessively with 50 ml of water and 50 ml of a saturated salinesolution in this order, and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressure,and the resulting concentrate was purified by silica gel columnchromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1(volume ratio)) to obtain 5.48 g of methyl2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate (isolation yield: 71%) as ayellowish oily product with a purity of 97% (areal percentage by highperformance liquid chromatography).

Methyl 2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate is a novel compoundhaving the following physical properties.

EI-MS (m/e); 192 (M-NO₂), CI-MS (m/e); 239 (M+1)

FT-IR (liquid film method, cm⁻¹); 3300 to 2800, 2255, 1758, 1594, 1533,1347, 1262, 1222

¹H-NMR (CDCl₃, δ (ppm)); 3.88 (3H, s), 5.71 (1H, s), 7.3 to 7.4 (1H, m),7.45 to 7.55 (1H, m), 8.3 to 8.4 (1H, m)

Example 5

In the similar device as in Example 3 were charged 6.98 g (62.2 mmol) ofpotassium t-butoxide and 15 ml of dimethyl sulfoxide under argonatmosphere, and then, 7.30 ml (62.2 mmol) of methyl acetoacetate with apurity of 99% was gradually added dropwise to the mixture over 5 minuteswhile stirring under ice-cooling. The temperature of the mixture wasraised to 25 to 30° C., and after stirring for 15 minutes, 5.00 g (30.8mmol) of 2,4-difluoronitrobenzene with a purity of 98% was graduallyadded dropwise to the mixture over 10 minutes, and the mixture wasreacted at 40 to 45° C. for 15 minutes, and further at 50 to 55° C. for1.5 hours. After completion of the reaction, the mixture was cooled toroom temperature, 100 ml of ethyl acetate was added to the mixture, and5.13 ml (30.7 mmol) of 6 mol/l hydrochloric acid and 20 ml of water weregradually added dropwise to the mixture while stirring. Then, theorganic layer was separated, and washed with 30 ml of a saturated-salinesolution, and dried over anhydrous magnesium sulfate. After filtration,the filtrate was concentrated under reduced pressure, and the resultingconcentrate was purified by silica gel column chromatography (filler:Daisogel 1002W, eluent: toluene) to obtain 6.40 g (isolation yield: 75%,keto form:enol form=1:6.5) of methyl2-(5-fluoro-2-nitrophenyl)-2-acetoacetate as a yellowish oily productwith a purity of 92% (areal percentage by high performance liquidchromatography).

Methyl 2-(5-fluoro-2-nitrophenyl)-2-acetoacetate is a novel compoundhaving the following physical properties.

EI-MS (m/e); 213 (M-CH₂CO), CI-MS (m/e) 256 (M+1)

FT-IR (liquid film method, cm⁻¹); 3400 to 2300, 1736, 1655, 1619, 1527,1445, 1347, 1280, 1250, 1066, 884, 836

¹H-NMR (CDCl₃, δ (ppm));

keto form: 2.42 (3H, s), 3.81 (3H, s), 5.43 (1H, s), 7.10 to 8.25 (3H,m)

enol form: 1.87 (3H, s), 3.65 (3H, s), 6.95 to 7.05 (1H, m), 7.10 to7.25 (1H, m), 8.05 to 8.20 (1H, m), 12.90 (1H, s)

Example 6

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 200ml were charged 2.79 g (51.6 mmol) of sodium methoxide and 15 ml ofdimethyl sulfoxide under argon atmosphere, and then, while stirring atroom temperature, 5.16 g (51.6 mmol) of methyl cyanoacetate with apurity of 99% was gradually added dropwise over 5 minutes. Moreover, atroom temperature, to the mixture was gradually added dropwise 5.00 g(25.8 mmol) of 2,4-dichloronitrobenzene with a purity of 98%, and theresulting mixture was reacted at 40 to 48° C. for 10 minutes and at 65°C. for 2 hours. After completion of the reaction, the mixture was cooledto room temperature, 10 ml of ethylacetate was added to the mixture, and4.30 ml (25.7 mmol) of 6 mol/l hydrochloric acid and 20 ml water weregradually added dropwise while stirring. Then, the organic layer wasseparated, washed with 50 ml of a saturated saline solution, and driedover anhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure, and the resulting concentrate waspurified by silica gel column chromatography (filler: Daisogel 1002W,eluent: hexane:ethyl acetate=9:1 (volume ratio)) to obtain 6.11 g(isolation yield: 92%) of methyl2-(5-chloro-2-nitrophenyl)-2-cyanoacetate as yellowish crystals with apurity of 99% (areal percentage by high performance liquidchromatography).

Methyl 2-(5-chloro-2-nitrophenyl)-2-cyanoacetate is a novel compoundhaving the following physical properties.

Melting point; 98 to 100° C.

EI-MS (m/e); 210, 208 (M-NO₂), CI-MS (m/e); 257, 255 (M+1)

Elemental analysis; Carbon, 47.17%; Hydrogen, 2.73%; Nitrogen, 10.98%

(theoretical value (C₁₀H₇N₂O₄Cl); Carbon, 47.17%; Hydrogen, 2.77%;Nitrogen, 11.00%)

FT-IR (KBr method, cm⁻¹); 3200 to 2800, 2247, 1764, 1575, 1524, 1342,1270, 1220, 850

¹H-NMR (CDCl₃, δ (ppm)); 3.88 (3H, s), 5.68 (1H, s), 7.62 (1H, dd,J=2.2, 8.8 Hz), 7.77 (1H, d, J=2.2 Hz), 8.21 (1H, d, J=8.8 Hz)

Example 7

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 100ml were charged 6.98 g (62.2 mmol) of potassium t-butoxide and 15 ml ofdimethyl sulfoxide under argon atmosphere, and then, 7.30 g (62.2 mmol)of methyl acetoacetate with a purity of 99% was gradually added dropwiseto the mixture over 5 minutes under ice-cooling and stirring. Thetemperature of the mixture was raised to 25 to 30° C., and afterstirring for 15 minutes, 5.97 g (30.8 mmol) of 2,4-dichloronitrobenzenewith a purity of 99% was gradually added dropwise to the mixture, andthe mixture was reacted at 65 to 70° C. for 3 hours. After completion ofthe reaction, the mixture was cooled to room temperature, then, 100 mlof ethyl acetate was added to the mixture, and 5.13 ml (30.7 mmol) of 6mol/l hydrochloric acid and 20 ml of water were gradually added dropwiseto the mixture while stirring. Then, the organic layer was separated,and washed successively with 20 ml of water and 30 ml of a saturatedsaline solution in this order, and dried over anhydrous magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure, and the resulting concentrate was purified by silica gelcolumn chromatography (filler: Daisogel 1002W, eluent: toluene) toobtain 6.40 g of methyl 2-(5-chloro-2-nitrophenyl)-2-acetoacetate(isolation yield: 73%, keto form:enol form=1:8.5) as a yellowish oilyproduct with a purity of 95% (areal percentage by high performanceliquid chromatography).

Methyl 2-(5-chloro-2-nitrophenyl)-2-acetoacetate is a novel compoundhaving the following physical properties.

EI-MS (m/e); 231 (M-CH₂CO), CI-MS (m/e); 274, 272 (M+1)

FT-IR (liquid film method, cm¹); 3400 to 2500, 1659, 1618, 1526, 1444,1346, 1266, 1227, 858, 836

¹H-NMR (CDCl₃, δ (ppm));

Keto form: 2.42 (3H, s), 3.81 (3H, s), 5.34 (1H, s), 7.4 to 8.2 (3H, m)

Enol form: 1.87 (3H, s), 3.65 (3H, s), 7.30 (1H, d, J=2.2 Hz), 7.46 (1H,dd, J=2.2, 8.8 Hz), 7.98 (1H, d, J=8.8 Hz), 12.90 (1H, s)

Example 8

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 200ml were charged 6.51 g (47.2 mmol) of potassium carbonate, 20 ml ofN,N-dimethylformamide, 6.24 g (46.7 mmol) of dimethyl malonate with apurity of 99% and 5.00 g (30.8 mmol) of 2,4-difluoronitrobenzene with apurity of 98% under argon atmosphere, and under stirring, the mixturewas reacted at room temperature for one hour and further by raising to70° C. for 5 hours. After completion of the reaction, the mixture wascooled to room temperature, 100 ml of ethyl acetate was added to themixture, and 10.5 ml (62.8 mmol) of 6 mol/l hydrochloric acid wasgradually added dropwise to the mixture while stirring. Then, afteradding 50 ml of water to the reaction mixture, the organic layer wasseparated, and washed successively with 20 ml of water and 20 ml of asaturated saline solution in this order, and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure, and the resulting concentrate was purified by silicagel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethylacetate=9:1 (volume ratio)) to obtain 6.22 g (isolation yield: 73%) ofdimethyl 2-(5-fluoro-2-nitrophenyl)malonate as white crystals with apurity of 98% (areal percentage by high performance liquidchromatography).

Example 9

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 100ml were charged 8.29 g (60.0 mmol) of potassium carbonate, 30 ml ofacetonitrile, 8.09 g (60.0 mmol) of dimethyl malonate with a purity of99% and 5.00 g (30.0 mmol) of 2,4-difluoronitrobenzene with a purity of98% under argon atmosphere, and under stirring, the mixture was reactedat 70° C. for 10 hours. After completion of the reaction, the mixturewas cooled to room temperature, 50 ml of toluene was added to themixture, and 7.5 ml (90 mmol) of 12 mol/l hydrochloric acid wasgradually added dropwise to the mixture while stirring. Then, theorganic layer was separated, and washed successively with 20 ml of waterand 20 ml of a saturated saline solution in this order, and dried overanhydrous magnesium sulfate. After filtration, this organic layer wasanalyzed (absolute quantitative method) by high performance liquidchromatography, it was found that 6.61 g (reaction yield: 81%) ofdimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.

Example 10

The same reaction as in Example 9 was carried out except for changingthe organic solvent to tetrahydrofuran in Example 9. As a result, 6.65 g(reaction yield: 82%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate wasfound to be formed.

Example 11

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 500ml were charged 55.3 g (0.40 mol) of potassium carbonate, 200 ml ofN,N-dimethylformamide, 54.0 g (0.40 mol) of dimethyl malonate with apurity of 98% and 32.5 g (0.20 mmol) of 2,4-difluoronitrobenzene with apurity of 98% under argon atmosphere, and under stirring, the mixturewas reacted at 70° C. for 3 hours. After completion of the reaction, themixture was cooled to room temperature, 160 ml of toluene was added tothe mixture, and 50 ml (0.60 mol) of 12 mol/l hydrochloric acid wasgradually added dropwise to the mixture while stirring. Then, theorganic layer was separated, and washed successively with 50 ml of waterand 50 ml of a saturated saline solution in this order, and dried overanhydrous magnesium sulfate. After filtration, this organic layer wasanalyzed (absolute quantitative method) by high performance liquidchromatography, it was found that 45.3 g (reaction yield: 84%) ofdimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.

Example 12

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 100ml were charged 3.03 g (21.9 mmol) of potassium carbonate, 5.0 ml ofN,N-dimethylformamide, 2.17 g (21.7 mmol) of methyl cyanoacetate with apurity of 99% and 1.45 g (8.94 mmol) of 2,4-difluoronitrobenzene with apurity of 98% under argon atmosphere, and under stirring, the mixturewas reacted at 60° C. for 6 hours. After completion of the reaction, themixture was cooled to room temperature, 50 ml of ethyl acetate was addedto the mixture, and 2.9 ml (34.8 mmol) of 12 mol/l hydrochloric acid wasgradually added dropwise to the mixture while stirring. Then, theorganic layer was separated, and washed successively with 20 ml of waterand 30 ml a saturated saline solution in this order, and dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure, and the resulting concentrate waspurified by silica gel column chromatography (filler: Daisogel 1002W,eluent: toluene) to obtain 1.81 g (isolation yield: 84%) of methyl2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate as a yellowish oily productwith a purity of 99% (areal percentage by high performance liquidchromatography).

Example 13

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 100ml were charged 8.68 g (62.9 mmol) of potassium carbonate, 20 ml ofN,N-dimethylformamide, 7.30 g (62.2 mmol) of methyl acetoacetate with apurity of 99% and 5.00 g (30.8 mmol) of 2,4-difluoronitrobenzene with apurity of 98% under argon atmosphere, and under stirring, the mixturewas reacted at 25° C. for 5 hours. After completion of the reaction, themixture was cooled to room temperature, 100 ml of ethyl acetate wasadded to the mixture, and 15.7 ml (94.2 mmol) of 6 mol/l hydrochloricacid was gradually added dropwise to the mixture while stirring. Then,after adding 50 ml of water to the mixture, the organic layer wasseparated, and washed successively with 20 ml of water and 30 ml of asaturated saline solution in this order, and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure, and the resulting concentrate was purified by silicagel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethylacetate=9:1 (volume ratio)) to obtain 6.08 g (isolation yield: 76%) ofmethyl 2-(5-fluoro-2-nitrophenyl)-2-acetoacetate as a yellowish oilyproduct with a purity of 98% (areal percentage by high performanceliquid chromatography)

Example 14

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 200ml were charged 7.13 g (51.6 mmol) of potassium carbonate, 20 ml ofN,N-dimethylformamide, 5.06 g (50.6 mmol) of methyl cyanoacetate with apurity of 99% and 5.00 g (25.8 mmol) of 2,4-dichloronitrobenzene with apurity of 99% under argon atmosphere, and under stirring, the mixturewas reacted at 45° C. for 4 hours. After completion of the reaction, themixture was cooled to room temperature, 100 ml of ethyl acetate wasadded to the mixture, and 12.9 ml (77.4 mmol) of 6 mol/l hydrochloricacid was gradually added dropwise to the mixture while stirring. Then,after adding 50 ml of water to the mixture, the organic layer wasseparated, and washed with 50 ml of a saturated saline solution, anddried over anhydrous magnesium sulfate. After filtration, the filtratewas concentrated under reduced pressure, and the resulting concentratewas purified by silica gel column chromatography (filler: Daisogel1002W, eluent: hexane:ethyl acetate=20:1 (volume ratio)) to obtain 5.76g (isolation yield: 83%) of methyl2-(5-chloro-2-nitrophenyl)-2-cyanoacetate as white crystals with apurity of 95% (areal percentage by high performance liquidchromatography).

Example 15

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a dropping funnel and having an inner volume of 200ml were charged 7.13 g (51.6 mmol) of potassium carbonate, 20 ml ofN,N-dimethylformamide, 6.05 g (51.6 mmol) of methyl acetoacetate with apurity of 99% and 5.00 g (25.8 mmol) of 2,4-dichloronitrobenzene with apurity of 99% under argon atmosphere, and under stirring, the mixturewas reacted at 70° C. for 3 hours. After completion of the reaction, themixture was cooled to room temperature, 100 ml of ethyl acetate wasadded to the mixture, and 12.9 ml (77.4 mmol) of 6 mol/l hydrochloricacid was gradually added dropwise to the mixture while stirring. Then,after adding 30 ml of water to the mixture, the organic layer wasseparated, and washed with 30 ml of a saturated saline solution, anddried over anhydrous magnesium sulfate. After filtration, the filtratewas concentrated under reduced pressure, and the resulting concentratewas purified by silica gel column chromatography (filler: Daisogel1002W, eluent: hexane:ethyl acetate=40:1 (volume ratio)) to obtain 4.33g (isolation yield: 61%) of methyl2-(5-chloro-2-nitrophenyl)-2-acetoacetate as a yellowish oily productwith a purity of 98% (areal percentage by high performance liquidchromatography).

Example 16

In a flask made of glass equipped with a stirrer, a thermometer and agas inlet tube and having an inner volume of 100 ml were charged 3.93 g(14.2 mmol) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate synthesizedaccording to Example 1 with a purity of 98%, 0.5 g (0.12 mmol as apalladium atom) of 5% by weight palladium/carbon (49% hydrated product)and 50 ml of ethyl acetate under argon atmosphere. Then, the innersystem was replaced with hydrogen, and the mixture was reacted under ahydrogen pressure of 0.15 MPa at 20° C. for 2 hours. After completion ofthe reaction, the catalyst was filtered off by filtrating the reactionmixture and then the filtrate was concentrated under reduced pressure,and the resulting concentrate was purified by silica gel columnchromatography (filler: Daisogel 1002W, eluent: chloroform) to obtain2.76 g (isolation yield: 92%) of 5′-fluoro-3-methoxycarbonyloxindole aswhite crystals with a purity of 99% (areal percentage by highperformance liquid chromatography).

5-Fluoro-3-methoxycarbonyloxindole is a novel compound having thefollowing physical properties. Incidentally, from an integral valculusvalue by ¹H-NMR, a keto form and an enol form existed in heavychloroform with a ratio of 1:2.2.

Melting point; 142 to 143° C.

EI-MS (m/e); 209 (M+), CI-MS (m/e); 210 (M+1)

FT-IR (KBr method, cm⁻¹); 3300 to 2600, 1647, 1569, 1481, 1204, 1160,1108

¹H-NMR (CDCl₃, δ (ppm));

keto form: 3.82 (3H, s), 4.48 (1H, s), 6.81 to 6.88 (1H, m) 6.99 (1H,ddd, J=2.7, 8.5, 8.5 Hz), 7.08 to 7.13 (1H, m), 8.18 (1H, s)

enol form: 3.97 (3H, s), 6.81 to 6.88 (1H, m), 6.96 to 7.02 (1H, m),7.39 (1H, dd, J=2.3, 9.4 Hz), 8.24 (1H, s)

Example 17

In a flask made of glass equipped with a stirrer, a thermometer, areflux condenser and a gas inlet tube and having an inner volume of 500ml were charged 60.0 g (0.22 mol) of dimethyl2-(5-fluoro-2-nitrophenyl)malonate synthesized according to Example 1with a purity of 98% and 228 g of methanol under argon atmosphere. Understirring, while maintaining the temperature of the mixture to 40 to 45°C., 3.0 g (0.72 mmol in terms of the palladium atom) of 5% by weightpalladium/carbon (49% hydrated product) was added to the mixture. Then,while blowing hydrogen with a flow rate of 123 ml/min. and a normalpressure, the mixture was reacted at the same temperature for 3 hours.After completion of the reaction, the reaction mixture was filtered toremove the catalyst, the filtrate was concentrated under reducedpressure, and 80 ml of methanol and 240 ml of water were added to theresulting concentrate and cooled to 10° C. Then, after filtration of theprecipitated crystals, they were dried to obtain 54.5 g (isolationyield: 94%) of 5-fluoro-3-methoxycarbonyloxindole as white crudecrystals with a purity of 80% (analytical value by high performanceliquid chromatography)

Example 18

In a flask made of glass equipped with a stirrer, a thermometer, adropping funnel and a reflux condenser and having an inner volume of 500ml were charged 26.5 g (0.10 mol) of crude crystal of5-fluoro-3-methoxycarbonyloxindole synthesized according to Example 17with a purity of 80% (analytical value by high performance liquidchromatography), 66.9 g of methanol and 52.0 ml (0.31 mol) of 6 mol/lhydrochloric acid, and the mixture was reacted at 70 to 80° C. for 2hours. After completion of the reaction, the mixture was cooled to roomtemperature, 55.0 ml (0.44 mol) of 8 mol/l aqueous sodium hydroxidesolution was added to the mixture, and the resulting mixture was stirredat 40° C. for 30 minutes. Then, 8.3 ml (0.10 mol) of 12 mol/lhydrochloric acid was added to the resulting mixture. After removingmethanol under reduced pressure, the reaction mixture was cooled to 0 to5° C., then a solid was precipitated so that it was collected byfiltration. The resulting solid was recrystallized from isopropylalcohol/water to obtain 12.6 g (isolation yield: 80%) of5-fluorooxindole as white crystals with a purity of 99% (arealpercentage by high performance liquid chromatography).

Physical properties of 5-fluorooxindole were as follows.

Melting point; 141 to 142° C.

EI-MS (m/e); 151(M+), CI-MS(m/e); 152(M+1)

Elemental analysis; Carbon, 63.56%; Hydrogen, 4.02%; Nitrogen, 9.29%

(theoretical value (C₈H₆NOF); Carbon, 63.57%; Hydrogen, 4.00%; Nitrogen,9.27%)

FT-IR (KBr method, cm⁻¹); 3400 to 2500, 1700, 1633, 1485, 1317, 1195,745, 673, 591 ¹H-NMR (CDCl₃, δ (ppm)); 3.56 (2H, s), 6.75 to 6.85 (1H,m), 6.85 to 7.00 (2H, m), 9.03 (1H, brs)

UTILIZABILITY IN INDUSTRY

According to the present invention, a2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundcan be produced from a 2,4-dihalogenonitrobenzene compound with a simpleand easy method, whereby an industrially suitable process for preparinga 2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundcan be provided.

Moreover, according to the present invention, an industrially suitableprocess for preparing 5-fluorooxindole can be provided by a simple andeasy method from an easily available 2-(5-fluoro-2-nitrophenyl)malonicacid diester to obtain 5-fluorooxindole with a high yield.

1. A 5-fluorooxindole-3-carboxylic acid ester represented by a formula(2):

wherein R¹ is a group selected from the group consisting of anunsubstituted or substituted alkyl group having 1 to 10 carbon atoms, anunsubstituted or substituted cycloalkyl group having 3 to 7 carbonatoms, an unsubstituted or substituted aralkyl group having 7 to 10carbon atoms or an unsubstituted or substituted aryl group having 6 to14 carbon atoms.
 2. The 5-fluorooxindole-3-carboxylic acid esteraccording to claim 1, wherein R¹ is an unsubstituted or substitutedalkyl group having 1 to 10 carbon atoms.
 3. The5-fluorooxindole-3-carboxylic acid ester according to claim 1, whereinR¹ is an unsubstituted or substituted cycloalkyl group having 3 to 7carbon atoms.
 4. The 5-fluorooxindole-3-carboxylic acid ester accordingto claim 1, wherein R¹ is an unsubstituted or substituted aralkyl grouphaving 7 to 10 carbon atoms.
 5. The 5-fluorooxindole-3-carboxylic acidester according to claim 1, wherein R¹ is an unsubstituted orsubstituted aryl group having 6 to 14 carbon atoms.
 6. The5-fluorooxindole-3-carboxylic acid ester according to claim 1, whereinthe group for R¹ is substituted with at least one substituent selectedfrom the group consisting of an alkyl group, an aralkyl group, an arylgroup, an alkoxy group, an aryloxy group, a cyano group, a nitro groupand an amino group.
 7. The 5-fluorooxindole-3-carboxylic acid esteraccording to claim 1, wherein the group for R¹ is substituted with atleast one substituent selected from the group consisting of a methylgroup, an ethyl group, a propyl group, a benzyl group and a phenethylgroup.
 8. A process for preparing a2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundrepresented by a formula (6):

wherein R³, R⁴ and R⁵ are the same or different from each other and eachrepresents a hydrogen atom, an alkyl group, a cycloalkyl group, anaralkyl group or an aryloxy group; R⁶ represents an alkoxycarbonylgroup, an aralkyloxycarbonyl group, an aryloxycarbonyl group, an acylgroup or a cyano group; R⁷ represents an alkyl having 1 to 4 carbonatoms, an aralkyl group or an aryl group; and X² represents a halogenatom, which comprises reacting a 2,4-dihalogenonitrobenzene compoundrepresented by a formula (4):

wherein R³, R⁴ and R⁵ and X² have the same meanings as defined above andX¹ represents a halogen atom, with a 2-mono-substituted acetic acidester compound represented by a formula (5):

wherein R⁶ and R⁷ have the same meanings as defined above, in thepresence of at least one metal alkoxide or at least one metal inorganicacid salt, and an at least one organic solvent.
 9. The process forpreparing the 2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acidester compound according to claim 8, wherein the process is carried outin the presence of at least one metal alkoxide which includes a metalatom, said metal atom being a 1A Group atom, a 2A Group atom or a 3BGroup atom.
 10. The process for preparing the2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundaccording to claim 8, wherein the process is carried out in the presenceof at least one metal inorganic acid salt which includes a metal atom,said metal atom being an alkali metal atom or an alkaline earth metalatom.
 11. The process for preparing the2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundaccording to claim 8, wherein the process is carried out in the presenceof at least one metal inorganic acid salt which includes an inorganicacid which is a carbonic acid.
 12. The process for preparing the2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundaccording to claim 8, wherein the process is carried out in the presenceof at least one metal alkoxide which includes a metal atom selected fromthe group consisting of a lithium atom, a sodium atom, a potassium atom,a magnesium atom, a calcium atom and an aluminum atom.
 13. The processfor preparing the 2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acidester compound according to claim 8, wherein the process is carried outin the presence of at least one metal alkoxide which is selected fromthe group consisting of lithium methoxide, sodium methoxide, potassiummethoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide,magnesium methoxide, calcium methoxide and aluminum methoxide.
 14. Theprocess for preparing the 2-(5-halogeno-2-nitrophenyl)-2-substitutedacetic acid ester compound according to claim 8, wherein the process iscarried out in the presence of at least one inorganic acid salt selectedfrom the group consisting of sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogen carbonate, magnesiumcarbonate, calcium carbonate, sodium phosphate and sodium hydrogenphosphate.
 15. The process for preparing the2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundaccording to claim 11, wherein the inorganic acid salt is sodiumcarbonate or potassium carbonate.
 16. The process for preparing the2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester compoundaccording to claim 8, wherein the process is carried out in the presenceof at least one metal alkoxide or at least one metal inorganic acid saltin an amount of 1.0 to 5.0 total moles based on the amount of the2,4-dihalogenonitrobenzene compound.
 17. The process for preparing the2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester accordingto claim 8, wherein the organic solvent is at least one solvent selectedfrom the group consisting of diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, hexane, cyclohexane, benzene, toluene, xylene,N,N-dimethylformamide, N,N′-dimethylimidazolidinone, acetonitrile,propionitrile and dimethyl sulfoxide.
 18. The process for preparing the2-(5-halogeno-2-nitrophenyl)-2-substituted acetic acid ester accordingto claim 17, wherein said at least one organic solvent is in an amountof 1 to 50 total weight based on the amount of the2,4-dihalogenonitrobenzene compound.
 19. A2-(5-halogeno-2-nitrophenyl)-2-acylacetate compound represented by theformula (7):

wherein R³, R⁴ and R⁵ are the same or different from each other and eachrepresents a hydrogen atom, a halogen atom, an alkyl group, a cycloalkylgroup, an aralkyl group or an aryloxy group; R⁷ represents an alkylgroup having 1 to 4 carbon atoms, an aralkyl group or an aryl group; X²represents a halogen atom; and R⁸ represents an alkyl group, an aralkylgroup or an aryl group.
 20. A2-(5-halogeno-2-nitrophenyl)-2-cyanoacetate compound represented by aformula (8):

wherein R³, R⁴ and R⁵ are the same or different from each other and eachrepresents a hydrogen atom, a halogen atom, an alkyl group, a cycloalkylgroup, an aralkyl group or an aryloxy group; R⁷ represents an alkylgroup having 1 to 4 carbon atoms, an aralkyl group or an aryl group; andX² represents a halogen atom.
 21. A process for preparing5-fluorooxindole-3-carboxylic acid ester represented by the formula (2)

wherein R¹ represents an alkyl group having 1 to 10 carbon atoms, acycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 7to 10 carbon atoms or an aryl group having 6 to 14 carbon atoms, whichcomprises cyclizing 2-(5-fluoro-2-nitrophenyl)malonic acid diesterrepresented by the formula (1):

wherein R¹ has the same meaning as defined above, and R² is the same ordifferent from R¹ and represents an alkyl group having 1 to 10 carbonatoms, a cycloalkyl group having 3 to 7 carbon atoms, an aralkyl grouphaving 7 to 10 carbon atoms or an aryl group having 6 to 14 carbonatoms, under reductive conditions.
 22. The process for preparing5-fluorooxindole-3-carboxylic acid ester according to claim 21, whereinthe cyclization under the reductive conditions is carried out under ahydrogen atmosphere in the presence of a catalyst.
 23. The process forpreparing 5-fluorooxindole-3-carboxylic acid ester according to claim22, wherein the catalyst is a material containing at least one metalatom selected from the group consisting of palladium, platinum andnickel.
 24. The process for preparing 5-fluorooxindole-3-carboxylic acidester according to claim 22, wherein the catalyst is in an amount of0.01 to 1.0% by weight based on the amount of the2-(5-fluoro-2-nitrophenyl)malonic acid diester.
 25. The process forpreparing 5-fluorooxindole-3-carboxylic acid ester according to claim22, wherein the catalyst is in an amount of 0.05 to 0.5% by weight basedon the amount of the 2-(5-fluoro-2-nitrophenyl)malonic acid diester. 26.The process for preparing 5-fluorooxindole-3-carboxylic acid esteraccording to claim 25, wherein the catalyst is selected from the groupconsisting of palladium/carbon, palladium/barium sulfate, palladiumhydroxide/carbon, platinum/carbon, palladium-platinum/carbon, platinumoxide and Raney nickel.
 27. The process for preparing5-fluorooxindole-3-carboxylic acid ester according to claim 25, whereinthe catalyst is palladium/carbon.
 28. The process for preparing5-fluorooxindole-3-carboxylic acid ester according to claim 22, whereinthe cyclization is carried out at a pressure of 0.1 to 5 MPa and at atemperature of 20 to 80° C.
 29. The process for preparing5-fluorooxindole-3-carboxylic acid ester according to claim 22, whereinthe cyclization is carried out at a pressure of 0.1 to 2 MPa and at atemperature of 30 to 60° C.
 30. The process for preparing5-fluorooxindole-3-carboxylic acid ester according to claim 22, whereinthe cyclization is carried out in the presence of at least one solventselected from the group consisting of water, methanol, ethanol, methylacetate, ethyl acetate, benzene, toluene, tetrahydrofuran and dioxane.31. The process for preparing 5-fluorooxindole-3-carboxylic acid esteraccording to claim 30, wherein the solvent is selected from the groupconsisting of water, methanol and ethanol.
 32. The process for preparing5-fluorooxindole-3-carboxylic acid ester according to claim 32, whereinthe catalyst is in an amount of 3 to 50-fold weight based on the amountof the 2-(5-fluoro-2-nitrophenyl)malonic acid diester.